Significance Simian immunodeficiency virus (SIV) infection of macaques is a unique model for human immunodeficiency virus (HIV) infection and vaccine development. Objective The use of IFN-( and other lymphokines to enhance the safety and efficacy of live attenuated vaccines for AIDS is the major and long term objective of these projects. Results We constructed and characterized a number of SIV vectors with a deletion in the nef gene (SIV(nef) and expressing interferon-( under SV40 early promotor or SIV 5[unreadable]LTR (SIVHyIFN). Rhesus macaques vaccinated with SIVHyIFN have a lower viral load than a group similarly immunized with SIV(nef. Viral loads remained low in the SIVHyIFN -vaccinated group even though SIV expressing IFN-( could not be isolated after 6 weeks post-immunization in these animals. All immunized and two naive control macaques became infected when challenged with virulent SIVmac251 at 25 weeks post-vaccination. In contrast to the two naive controls that died by 12 and 18 weeks post-challenge, post-challenge cell-associated virus load was significantly lower in SIVHyIFN-immunized animals than in the group vaccinated with SIV(nef. Also, the oral administration of SIVHyIFN was non-pathogenic for newborn macaques and induced protective immunity against challenge with virulent SIVmac251 in one macaque that had low level sporadic SIVHyIFN viremia. These findings indicate that cytokine-expressing viruses can provide a novel approach for development of safe and efficacious live attenuated vaccines for AIDS. Future Directions SIV with a deletion in the nef gene and expressing IFN-( is safer and more efficacious for both neonatal and juvenile macaques against simian AIDS. The next generation recombinant SIV vectors, that express IFN-( and have stable genomes, are being constructed for developing safer and efficacious live-attenuated vaccines for AIDS. KEYWORDS AIDS vaccines, recombinant SIV vectors, IFN-(, lymphokines, immune response, macaques;